Gut microbiota-derived trimethylamine N-oxide is associated with the risk of all-cause and cardiovascular mortality in patients with chronic kidney disease: a systematic review and dose-response meta-analysis

Abstract

Background Trimethylamine N-oxide (TMAO) derived from gut microbiota causes kidney-heart damage in chronic kidney disease (CKD) patients. However, it is controversial whether CKD patients with higher TMAO are associated with a higher risk of death. We aimed to assess the correlation between circulating TMAO concentration and the risk of all-cause and cardiovascular death in CKD patients of different dialysis statuses and different races by dose-response analyses, and the underlying mechanisms were also explored by analyzing the correlations of TMAO with glomerular filtration rate (GFR) and inflammation. Method PubMed, Web of Science, and EMBASE were systematically searched up to 1 July 2022. A total of 21 studies involving 15,637 individuals were included. Stata 15.0 was used to perform the meta-analyses and dose-response analyses with extracted data. Subgroup analyses were conducted to recognize possible sources of heterogeneity. Results The risk of all-cause mortality was increased in non-dialysis CKD patients (RR = 1.26, 95%CI = 1.03–1.54, p = 0.028) and non-black dialysis patients (RR = 1.62, 95%CI = 1.19–2.22, p = 0.002) with the highest circulating TMAO concentration, and the association was confirmed to be linear. In addition, an increased risk of cardiovascular mortality was also found in non-black dialysis patients with the highest circulating TMAO concentration (RR = 1.72, 95%CI = 1.19–2.47, p = 0.004), likewise, a linear association was identified. However, for dialysis patients including blacks with high TMAO concentrations, there was no significant increase in either all-cause mortality (RR = 0.98, 95%CI = 0.94-1.03, p = 0.542) or cardiovascular mortality (RR = 0.87, 95% CI = 0.65–1.17, p = 0.362). Meanwhile, we verified strong correlations between TMAO and both GFR ( r = −0.49; 95% CI= −0.75, −0.24; p < 0.001) and inflammatory markers ( r = 0.43; 95% CI= 0.03, 0.84; p = 0.036) in non-dialysis patients. Conclusions Increased circulating TMAO concentrations increase the risk of all-cause mortality in non-dialysis and non-black dialysis CKD patients. Moreover, elevated TMAO levels raise the cardiovascular mortality risk in non-black dialysis patients. Key messages Non-dialysis and non-black dialysis CKD patients with higher circulating TMAO concentrations are associated with an increased risk of all-cause mortality. Non-black dialysis patients with higher concentrations of TMAO are associated with an increased risk of cardiovascular mortality. Circulating TMAO concentrations have a strong negative correlation with GFR and a positive correlation with inflammation bio...

Role of symbiotic microbiota dysbiosis in the progression of chronic kidney disease accompanied with vascular calcification

“…They identified a panel of five microbial markers that could potentially serve as non-invasive diagnostic tools for CKD across various regions of China. Trimethylamine N-oxide, an intriguing metabolite of gut microbiota, has been found to be positively associated with the risk of all-cause mortality in both non-dialysis and non-black dialysis CKD patients (Li et al, 2023). Consequently, interventions targeting gut microbiota dysbiosis may lead to the regulation of gut microbiota, potentially contributing to favorable clinical outcomes in patients with CKD (Sumida et al, 2023).…”

The Interplay Between Dietary Choline and Cardiometabolic Disorders: A Review of Current Evidence

“…Serum TMAO levels are elevated among CKD patients due to the decreased renal clearance. In addition, gut microbiota alterations have been documented to occur in patients with CKD [ 18 , 84 ]. The brain-gut-kidney axis supports the notion that changes in the composition of the gut microbiota are involved in the increased production and decreased renal elimination of uremic toxic metabolites, such as TMAO, p-Cresyl-sulfate (p-CS), and indoxyl-sulfate (IS) [ 18 , 84 ].…”

“…In addition, gut microbiota alterations have been documented to occur in patients with CKD [ 18 , 84 ]. The brain-gut-kidney axis supports the notion that changes in the composition of the gut microbiota are involved in the increased production and decreased renal elimination of uremic toxic metabolites, such as TMAO, p-Cresyl-sulfate (p-CS), and indoxyl-sulfate (IS) [ 18 , 84 ]. Figure 2 describes the main mechanisms through which CVD and CKD are suggested to be associated with choline intake.…”

An Overview of Chronic Kidney Disease Pathophysiology: The Impact of Gut Dysbiosis and Oral Disease

“…For the metabolism of substances such as choline, phosphatidylcholine, and L-carnitine ingested with the diet, the human body does not have an endogenous enzyme kit, and specific intestinal microorganisms transform them into TMA, which is absorbed into the circulation and reaches the liver, where it is oxidized by flavin monooxygenase in TMAO, and finally excreted by the kidneys [137]. For its atherogenic action, TMAO is now recognized as one of the most important independent risk factors for CVD, as well as for the development of cardiovascular complications typical of CKD, and elevated plasma levels of this metabolite have been related to an increase in major cardiac adverse events and mortality in the general population and patients with CKD [72,73,138]. Elevated TMAO concentrations are positively correlated with long-term mortality risk in patients with CKD, atherosclerosis, and heart failure.…”

“…UTs promote the imbalance between the formation of ROS and antioxidant capacity, which leads to excessive OS [160]. Increased ROS induce inflammation, endothelial dysfunction, atherosclerosis, and fibrosis and are considered powerful promoters of CKD [77,138,161].…”